The Hallmarks of Cancer Theresa L. Hodin, Ph.D. Clinical Research Services Theresa.Hodin@RoswellPark.org
Hippocrates
Cancer surgery, circa 1689
Cancer Surgery Today
1971: Nixon declares War on Cancer 2001: Andrew von Eschenbach eliminate suffering and death by 2015 2004: Why We're Losing The War On Cancer Fortune Magazine.. Age-adjusted Death rates
Cancer is the Result of a Multistep Process Colon Adenoma to Carcinoma Ductal Carcinoma in situ to Invasive Breast Cancer Prostatic intraepithelial neoplasia to Prostate Cancer normal --> ---> early ---> mid ----> late ---> carcinoma --> mets adenoma adenoma adenoma
What are the underlying events and how do they come about????? normal --> ---> early ---> mid ----> late ---> carcinoma --> mets adenoma adenoma adenoma
Review The Hallmarks of Cancer Douglas Hanahan* and Robert A. Weinberg Cell, Vol. 100, 57 70, January 7, 2000
Review Hallmarks of Cancer: The Next Generation Douglas Hanahan* and Robert A. Weinberg Cell, Vol. 144, 646 674, March 4, 2011
Acquired Capabilities of a Cancer Cell Cell 100, 57 70
Hanahan &Weinberg Cell 100:57 2000
In Vitro Studies
Oncogenes mutated forms of normal cellular genes generally involved in promoting cell proliferation. These mutations result in dominant gain of function. Tumor Suppressor genes genes whose normal function in regulating proliferation is to stop it. Mutation results in recessive loss of function.
Carcinogenesis: The accumulation of multiple genetic alterations that drives a normal cell to malignancy. Hypothesis: Mutation in one gene associated with each step in progression.
Early Molecular Model of Tumor Progression - Vogelstein
Karyotype Chaos
Tumor Heterogeneity Breastcancer.org
Acquired Capabilities of a Cancer Cell Cell 100, 57 70
Normal Mitogenic Growth Stimulation Transmembrane Receptor Signal Transduction Proteins Growth Factor Nucleus Cytoplasm
Strategies of Tumor Cell Self- Sufficiency
Insensitivity to Anti-Growth Signals Anti-Growth Signal such as TGFβ Smads Mad Max Myc Max TGFβR prb Cell Proliferation
Regulation of Apoptosis Sensor Molecules Mitochondrion Fas ligand Antiapoptosis signal Proapoptosis signal Fas p53? Bcl2 Bax Effector Molecules Cell Death
Limitless Replicative Potential Telomeres (TTAGG)nTTAGGTTAGGTTAGGTTAGGTTAGG (TTAGG)nTTAGGTTAGGTTAGGTTAGG (TTAGG)nTTAGGTTAGGTTAGG (TTAGG)nTTAGGTTAGG
Angiogenesis Angiogenic Factors Antiangiogenic Factors Region of insufficent blood supply
Invasion and Metastasis I Integrins Cell Adhesion Molecules (Adherens)
Invasion and Metastasis II Extracellular Proteases
Invasion and Metastasis III A. Epithelial-Mesenchymal Transition Normally during embryonic morphogenesis Epithelial cells acquire Mesenchymal traits Loss of adherens junctions Change in cellular morphology Expression of proteases Increased motility B. Collective Invasion C. Amoeboid Invasion Partial EMT?
Reductionist View of a Tumor
Realistic View of a Tumor
Immune Evasion Some data supports: Selective killing of highly immunogenic tumors, leaving weakly immunogenic ones Tumors disable parts of the immune system by secreting or recruiting cells that secrete immunosuppressive factors (ex. TGF B) Tumor cells down-regulate expression of MHC genes
Tumor-Promoting Inflammation Tumor- infiltrating immune cells provide factors which: Stimulate growth Inhibit cell death Promote angiogenesis Degrade extracellular matrices Induce epithelial-mesenchymal transition Damage DNA (reactive oxygen species)
Deregulating Cellular Energetics
PET SCAN
Cancer - evolution at a vastly accelerated rate favoring the growing tumor mass over the organism. Genomic Instability introduces genomic alterations and Natural Selection chooses the fittest tumor to survive.